The present invention relates to optically active cephalosporin analogs and, more particularly, it pertains to optically active compounds of cephalosporin analogs represented by the general formula (I) ##STR1## (wherein R.sub.1 represents a substituted or unsubstituted, saturated or unsaturated six-membered carbocyclic or five-membered heterocyclic group, R.sub.2 represents a hydrogen or a protective group of carboxylic acid, Hal represents a halogen atom, X represents a hydrogen, a lower alkyl group, a hydroxy group, a carboxyl group or an amino group and the hydrogens at the 6- and 7-positions have cis configuration), pharmaceutically acceptable salts thereof, and a process for producing the same.
The compounds represented by the general formula (I), (II), . . . may be named Compound [I], Compound [II], . . . , respectively.
Heretofore, a carbacephem compound, which is named according to the nomenclature in J. Am. Chem. Soc. 96, 7584 (1974), wherein the sulfur atom of cephalosporin is substituted with a carbon atom and which has a substituted methyl group at the 3-position is described in the above reference and J. Med. Chem. 20, 551 (1977). However, no compound having especially strong antibacterial activity has been reported.
The present inventors have succeeded in preparing carbacephem compounds having various substituents at the 4-, 5- or 3-position. The compounds are described in the specification of Japanese Patent Application (referred to as "JPA", hereinafter) No. 34696/78 [Japanese Patent Unexamined Patent Application (referred to as "JPUPA", hereinafter) No. 128591/79], JPA No. 122403/78 (JPUPA No. 49376/80), JPA No. 133072/78 (JPUPA No. 59186/80), JPA No. 162005/78 (JPUPA No. 87788/80), JPA No. 162008/78) (JPUPA No. 87791/80), JPA No. 8408/79 (JPUPA No. 100384/80), German Offenlegungsschrift No. 2911786 and U.S. Patent Application Ser. No. 023,645 now U.S. Pat. No. 4,291,164. Especially, optically inactive cephalosporin analogs are described in detail in Japanese Patent Application No. 92035/79 (U.S. Patent Application Ser. No. 171,297).
Further, novel acylated carbacephems which have strong antibacterial activities are describes in JPA No. 34696/78 (JPUPA No. 128591/79), JPA No. 122402/78 (JPUPA No. 49375/80), JPA No. 127027/78 (JPUPA No. 53290/80), JPA No. 133071/78 (JPUPA No. 59185/80), JPA No. 162006/78 (JPUPA No. 87789/80), JPA No. 162007/78 (JPUPA No. 87790/80), JPA No. 8409/79 (JPUPA No. 100391/80), JPA No. 92035/79 and U.S. Patent Application Ser. No. 23,646.
However, cephalosporin analogs mentioned above are prepared by synthetic methods using optically inactive starting compounds, and they are in principal optically inactive dl [represented by (.+-.)] compounds.
That is, compounds represented by the general formula (III) ##STR2## wherein R.sub.2 and Hal have the same significance as defined above and the hydrogen atoms at the 6- and 7-positions have cis configuration are present as a mixture of equal amounts of the mirror image compounds represented by the formulae (III-1) and (III-2). ##STR3##
Therefore, all acyl compounds derived from such carbacephem compounds are optically inactive.
On the other hand, a compound wherein an optically active acyl group such as D-phenylglycyl group is introduced to an optically inactive carbacephem compound, for example, the compound represented by the general formula (IV) ##STR4## is separated to diastereoisomers (JPA No. 92035/79). The diastereoisomers are assumed to have the absolute structural formulae (IV-1) and (IV-2). ##STR5## However, this method is complicated because in the preparation of Compound [IV], protection and elimination processes of amino group or carbonyl group are required.
Accordingly, there is a demand for optically active analogs and methods for production thereof. A method of producing optically active carbacephem compounds using culture broth of the same microorganism as those in the present invention or a treated matter thereof is described in JPA Nos. 14534/79 (JPUPA No. 108877/80), 14533/79 (JPUPA No. 108872/80) and 45897/79 and U.S. Patent Application Ser. No. 119,451 now U.S. Pat. No. 4,316,958 and 119,441 now abandoned. The method described in JPA Nos. 14533/79 and 14534/79 is complicated in the processes.
On the other hand, in the specification of JPA No. 45897/79, a method of producing optically active acyl derivative, for example, a compound represented by the general formula (IV-1) wherein Cl at the 3-position is H, by introducing an acyl group into the compound represented by the general formula (III) or (III-1) wherein Hal at the 3-position is H with a microorganism having an ability of acylating with optical selectivity is described.
To this end, it has now been found that the optically active compound of the cephalosporin analogs represented by the general formula (I) can be prepared using a microorganism capable of acylating with optical selectivity the compound represented by the general formula (III) or (III-1).